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Light is an essential natural factor of fish growth and development. A light regime in indoor aquaculture is critical for sustainable fish production. This research aimed to investigate the effect of light intensity and photoperiod on the growth performance and stress response of Nile tilapia (Oreochromis niloticus), which is an important commercial species, in a recirculating aquaculture system (RAS). Fingerlings with an average weight of 5 ± 0.9 g were randomly assigned to nine 1.5 m3 tanks with 145 fish in each tank, cultured under different light intensities (1000, 2000, and 3000 lx) and photoperiods (12L:12D, 18L:6D, 24L:0D), and fed to apparent satiation twice a day for 160 days. The growth of tilapia subjected to 2000 lx was significantly better than that exposed to 1000 and 3000 lx (P 0.05). Light intensity and photoperiod manipulation did not cause a significant chronic stress response in tilapia. This study demonstrated that light intensity, especially at 2000 lx, and photoperiod manipulation could stimulate the growth of tilapia in the RAS and significantly affect economic profitability. This study also served as an important reference for tilapia indoor aquaculture.

Nitric oxide (NO)—the product of arginine metabolism catalyzed by nitric oxide synthases (NOS)—is a well-known neurotransmitter which plays an important role in metabolism and amino acid transportation in the nervous system. In particular, it can inhibit monoamine neurotransmitter transportation which affects animal behavior, especially social behavior. Shoaling—is a one kind of social behavior. It is a behavior that individual fish choose to join with their group within two factors; food and predation risk. Shoaling fish has quickly responded to predator and increased the change in feeding competition. In addition, shoaling also effect to stress response on stock density of aquaculture system. The effect of NO molecular signaling on the dopamine pathway was investigated using zebrafish (Danio rerio) as a model organism. Our aim was to understand the role of NOS and NO in shoaling behavior, which is typical of zebrafish. The concentration of NO in the zebrafish brain was modulated using a knockout for the neuronal NOS gene, and NO production was induced through treatment with L-arginine. The existence of NO in the zebrafish brain was confirmed by using a fluorescent probe. Dopamine concentration in the brain was measured by UPLC tandem mass spectrometer. We measured shoaling cohesion of all individual fish of D. rerio, using average distance between all pairs of fish (nearest neighbor distance) and analyzed tracking by Zebralab ViewPoint software. Collectively, our results suggest that a lower level of NO was associated with a higher level of dopamine, which in turn leads to the shoaling behavior.

Background and Purpose: It is still unclear whether the residual cholesterol and inflammatory risk in the acute phase is associated with prognosis of stroke. We aimed to investigate the proportion and relative contribution of residual cholesterol and inflammatory risk, determined by baseline low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hsCRP) levels, to the risk of recurrent stroke and poor functional outcome at 1 year. Methods: In this prospective multicenter cohort study, 10 499 consecutive acute ischemic stroke and transient ischemic attack patients with levels of LDL-C and hsCRP were enrolled. Patients were divided into 4 groups: residual cholesterol risk only (LDL-C ≥2.6 mmol/L and hsCRP Results: The relative proportions of patients with RIR only, residual cholesterol risk only, both risk, and neither were 21.3%, 23.7%, 14.4%, and 40.6%, respectively. RIR only was independently associated with recurrent stroke (adjusted hazard ratio, 1.18 [95% CI, 1.00–1.40]; P =0.05). The association was slightly attenuated after further adjusting for usage of antiplatelet agent and statin during 1-year follow-up in addition to the traditional risk factors (hazard ratio, 1.31 [95% CI, 0.99–1.76]; P =0.07). When applying the LDL-C cutoff value of 1.8 mmol/L in the sensitivity analyses, such association in large-artery atherosclerosis subtype was more significant (adjusted hazard ratio, 1.69 [95% CI, 1.06–2.67]; P =0.03). Patients with RIR only also had increased risk of poor functional outcome (adjusted odds ratio, 1.43 [95% CI, 1.24–1.64]; P Conclusions: In the patients with acute ischemic stroke or transient ischemic attack, RIR only could be predictive for recurrent stroke, especially for those with large-artery atherosclerosis, and poor functional outcome.

Background With the trend that cosmetics containing natural extracts are favored by consumers, many natural herbs are used in cosmetics to enhance the moisturizing and whitening properties of cosmetics. Dendrobium officinale is the stem of the orchid Dendrobium officinale. In China, it is considered as a tonic beneficial to human health. Its main components are Dendrobium polysaccharides, alkaloids, phenanthrene, etc. Its extract has good skin coating comfort and has the potential to be developed as cosmetic raw materials. Objective To investigate the antioxidant activity, tyrosinase inhibitory activity, and ultraviolet absorption capacity of the fermentation extract of Dendrobium officinale fermented by different microorganisms, so as to provide the basis for Dendrobium officinale as functional cosmetic raw materials. Methods The fermentation of Dendrobium officinale was carried out by yeast, Lactobacillus, Bacillus subtilis, and the mixed bacteria (prepared according to the mass ratio of 1:1:1). Compared with the non-fermentation group, the contents of polysaccharides, flavonoids, and polyphenols in the fermentation broth of Dendrobium officinale were determined by spectrophotometry, and the antioxidant activity to common free radicals, inhibition to tyrosinase, and absorption to ultraviolet B were determined. Results The fermentation effect of mixed strains on Dendrobium officinale was better than that of a single strain. The content of polysaccharide decreased, while the content of flavonoids and polyphenols increased in the fermentation broth of Dendrobium officinale. With the extension of fermentation time, the scavenging rate of ·OH, DPPH, ABTS free radical, the inhibition rate of tyrosinase, and the absorption of ultraviolet B of Dendrobium officinale fermentation broth first increased (0-3 days), and then decreased (4 days). On the third day of mixed fermentation, the contents of polysaccharides, flavonoids, and polyphenols in the fermentation broth of Dendrobium officinale were - 22.15%, + 118.20%, and +128.17%, respectively. The scavenging rate of ·OH, DPPH, ABTS free radical, tyrosinase inhibition rate and SPF value were increased by 43.03%, 60.05%, 94.87%, 340.85%, and 31.73%, respectively. Conclusions The fermentation broth of Dendrobium officinale is superior to the non-fermentation group in active ingredients, antioxidant activity, tyrosinase inhibition, and ultraviolet B absorption. It has the potential as a functional cosmetic raw material.

Purpose: Patients with HER2-positive (HER2+) metastatic breast cancer (MBC) have poor prognoses. Pyrotinib has shown promising antitumor activity in MBC to improve progression-free survival (PFS). However, findings based on real-world data to analyze whether pyrotinib affects overall survival (OS) remain scarce. Experimental Design: This real-world study is an exploratory analysis of brain metastasis (BM) and the final update of our preceding study of 168 patients with HER2+ MBC. PFS, OS, tumor mutation burden (TMB), clinical benefit rate (CBR), and overall response rate (ORR) were analyzed. Results: Pyrotinib treatment led to a median PFS time of 8.00 months and a median OS of 19.07 months in the 168 participants. High TMB was associated with poor OS (P = 0.0072) and PFS (P = 0.0028). In the 39 patients with BM, the median PFS and OS were 8.67 and 13.93 months, respectively. The surgery/radiation (S/R) group of patients with BM had prolonged survival (PFS: 9.97 vs. 7.73 months P = 0.19; OS: 20.67 vs. 12.43 months P = 0.021) compared with the no surgery/no radiation group (NS/NR). The CBR was 58.6% (S/R) vs. 41.4% (NS/NR), while the ORR was 24.1% (S/R) vs. 31.0% (NS/NR). Conclusions: Pyrotinib shows promise as a novel pan-HER2 tyrosine kinase inhibitor (TKI) for the treatment of BM and should be evaluated further. Surgical or radiotherapy in combination with pyrotinib was found to statistically improve OS in our cohort. TMB could be an exploratory biomarker for predicting PFS and OS, but its clinical application still needs further verification.

Objective The aim of this study was to find out the relationship between serum biomarkers and cerebral collateral status in acute ischemic stroke with cerebral large artery atherosclerosis. Methods We enrolled patients with ischemic stroke due to large artery atherosclerosis within 7 days of symptom onset, age 18-80 years, from August 2016 to December 2017. Twelve biomarkers representing different pathophysiological mechanisms were tested after admission. Whole-brain perfusion combined with multiphase computed tomography angiography was performed to assess cerebral collateral structure and function. Results Fifty-two patients completed the test of candidate biomarkers and recruited in this study. The mean age was 55.0 (11.1) years, 42 (80.8%) patients were male, 20 (38.5%) had poor collateral, 36 (69.2%) patients had anterior circulation stenosis or occlusion. Compared with poor collateral group, the level of MMP-9 (135,475.00 pg/ml vs. 103,612.00 pg/ml, p = 0.040) and PGF (5.75 pg/ml vs. 3.46 pg/ml, p = 0.046) was significantly higher in good collateral group. The adjusted OR (95%CI) of MMP-9 and PGF were 5.533 (1.10-27.74, p = 0.038), 7.73 (1.41-42.39, p = 0.018), respectively. sTie-2 level had a positive correlation with proportion of Tmax 4-6 (r = 0.302, p = 0.033) and HMW-KGN had negative correlation with proportion of Tmax 6-8 (r = -0.338, p = 0.02). After adjustment, the correlation of sTie-2 level and proportion of Tmax 4-6 was statistically significant (p = 0.003), and correlation of HMW-KGN and Tmax6-8 was not statistically significant (p = 0.056). Discussion Serum PGF and MMP-9 levels may correlate with collateral status based on MP-CTA in acute ischemic stroke patients with cerebral large artery atherosclerosis. Higher PGF and MMP-9 concentration associated with good collateral status.

Colorectal cancer (CRC) is a frequently occurring digestive system cancer and postoperative tumor metastasis and recurrence are the main reasons for the failure of CRC treatment. The aim of this study was to identifying and validating key genes associated with metastatic recurrence of CRC. RNA expression of three datasets (GSE17538, GSE32323, and GSE29623) was used for biomarker discovery. We identified integrin‐binding sialoprotein (IBSP) as a candidate biomarker which was validated in three clinical cohorts (GSE41258, GSE21510, and GSE39582) and our clinical specimens. The results suggested that IBSP expression significantly increased at mRNA and protein levels among CRC cases, which was associated with metastatic recurrence, metastasis, high risk of recurrence, and poor survival in CRC. Consistent results were obtained in CRC cells. The relative level of serum IBSP evidently increased among CRC patients relative to normal controls, and downregulated after operation. As suggested by gene set enrichment analysis (GSEA), the IBSP level was associated with cell‐matrix adhesion in CRC. Functional experiments in vitro showed that IBSP promoted the growth and aggressiveness of CRC, and the potential mechanism by which IBSP promoted carcinogenesis of CRC was the abnormal activation of Fyn/β‐catenin signaling pathway. To sum up, findings in the present work indicate that IBSP can serve as the candidate biomarker for the diagnosis, treatment, and prognosis of CRC., In this study, we identified and validated IBSP as a key gene associated with metastatic recurrence of CRC which might serve as the candidate biomarker for the diagnosis, treatment, and prognosis of CRC. Our results suggested that IBSP expression significantly increased at mRNA and protein levels among CRC cases, which was associated with metastatic recurrence, metastasis, high risk of recurrence, and poor survival in CRC. Functional experiments in vitro showed that IBSP promoted the growth and aggressiveness of CRC, and the potential mechanism by which IBSP promoted carcinogenesis of CRC was the abnormal activation of Fyn/β‐catenin signaling pathway.

Background and Purpose: Intraluminal thrombus (ILT) is an emerging imaging marker in acute ischemic stroke. We aimed to investigate the association of ILT with outcomes of acute large vessel occlusion (LVO) patients receiving endovascular treatment. Methods: Acute LVO stroke patients who underwent endovascular treatment within 24 hours, in a prospective, nationwide registry were enrolled. Pretreatment digital subtraction angiography was reviewed for the presence of ILT. The primary outcome was 90-day functional dependence (modified Rankin Scale scores, 3–6). Secondary outcomes included 24-hour LVO, 90-day death, and symptomatic intracranial hemorrhage. Results: Among 711 patients enrolled, 75 (10.5%) with ILT were less likely to have 90-day functional dependence compared with those without ILT (adjusted odds ratio, 0.53 [95% CI, 0.31–0.90]; P =0.021). The same trend was found among those with successful reperfusion (modified Thrombolysis in Cerebral Infarction 2b–3; P =0.008) but not in those without successful reperfusion ( P =0.107). Presence of ILT was also independently associated with a lower rate of 24-hour LVO (adjusted odds ratio 0.34 [95% CI, 0.13–0.89]; P =0.028). However, those with or without ILT had similar risks of symptomatic intracranial hemorrhage and 90-day death. Conclusions: Among acute LVO patients receiving endovascular treatment, pretreatment ILT-positive patients may have a better 90-day functional outcome (versus ILT-negative) but similar risk of death and symptomatic intracranial hemorrhage. The possibly favorable effect of ILT patients remained in those with successful reperfusion. Registration: URL: http://www.chictr.org.cn ; Unique identifier: ChiCTR1900022154.

Background and purposeCurrent randomised controlled trials (RCTs) showed an uncertain benefit of haemostatic therapy on preventing haematoma expansion and improving the outcome in patients with intracerebral haemorrhage (ICH). This meta-analysis aims to systematically evaluate the effect of haemostatic agents on the prevention of haemorrhage growth in patients with high-risk spontaneous ICH predicted by CT signs in RCTs.MethodsA comprehensive search of PubMed, EMBASE and Cochrane library from 1 January 2005 to 30 June 2021 was conducted. RCTs that compared haemostatic agents with placebo for the treatment of spontaneous patients with ICH with high-risk haemorrhage growth were included. The primary endpoint was haematoma expansion at 24 hours. Other major endpoints of interest included 90-day functional outcome and mortality.ResultsThe meta-analysis included four RCTs that randomised 2666 patients with ICH with high-risk haemorrhage growth. Haemostatic therapy reduced the rate of haematoma expansion at a marginally statistically significant level when compared with placebo (OR 0.84; 95% CI 0.70 to 1.00; p=0.051). Subgroup analysis for patients with black hole sign on CT revealed a significant reduction of haematoma expansion with haemostatic therapy (OR 0.61; 95% CI 0.39 to 0.94; p=0.03). However, both the primary analysis and subgroup analyses showed that haemostatic therapy could not reduce the rate of poor functional outcome (modified Rankin Scale >3) or death.ConclusionsHaemostatic therapy showed a marginally significant benefit in reducing early haematoma expansion in patients with high-risk spontaneous ICH predicted by markers on CT scan. However, no significant improvement in functional outcome or reduction of mortality was observed.

Due to the lack of a suitable gene signature, it is difficult to assess the hypoxic exposure of HCC tissues. The clinical value of assessing hypoxia in HCC is short of tissue‐level evidence. We tried to establish a robust and HCC‐suitable hypoxia signature using microarray analysis and a robust rank aggregation algorithm. Based on the hypoxia signature, we obtained a hypoxia‐associated HCC subtypes system using unsupervised hierarchical clustering and a hypoxia score system was provided using gene set variation analysis. A novel signature containing 21 stable hypoxia‐related genes was constructed to effectively indicate the exposure of hypoxia in HCC tissues. The signature was validated by qRT‐PCR and compared with other published hypoxia signatures in multiple large‐size HCC cohorts. The subtype of HCC derived from this signature had different prognosis and other clinical characteristics. The hypoxia score obtained from the signature could be used to indicate clinical characteristics and predict prognoses of HCC patients. Moreover, we reveal a landscape of immune microenvironments in patients with different hypoxia score. In conclusion, we identified a novel HCC‐suitable 21‐gene hypoxia signature that could be used to estimate the hypoxia exposure in HCC tissues and indicated prognosis and a series of important clinical features in HCCs. It may enable the development of personalized counselling or treatment strategies for HCC patients with different levels of hypoxia exposure.

Jingqi Zhu,1,2,* Zhangwei Yang,2,* Xiaoli Chen,3,* Jie Liu,3 Liang Zheng,3 Lin Zhang,3 Jingjiang Pi,4 Gang Li,2 Tao Zhuang,3 Chang Liu,3 Yinglu Wang,3 Liping Liu,3 Lieying Fan,5 Paul Chan,6 Brian Tomlinson,7 Ying Li,4 Zhongmin Liu,3 Yuzhen Zhang3 1Department of Radiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 2Department of Radiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 3Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 4Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 5Department of Clinical Laboratory, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 6Division of Cardiology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 7Faculty of Medicine, Macau University of Science and Technology, Macau, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuzhen Zhang; Zhongmin LiuKey Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong New District, Shanghai, 200120, People’s Republic of ChinaTel +86-21-61569673Email yzzhang-tj@tongji.edu.cn; liu.zhongmin@tongji.edu.cnObjective: An association of atrial fibrillation (AF) with epicardial fat volume (EFV) varied in different ethnic groups. We evaluated the AF-related risk factors and its association with pericardial fat in Chinese patients.Methods: Patients referred for coronary computed tomography angiography (CCTA) in Shanghai East Hospital during 2012 to 2014 (n=2042, 43.8% women, mean age 65.0 years) had AF and cardiovascular risk assessment. Pericardial fat depots were measured from CT and the association of EFV with non-valvular AF risk factors was evaluated by multivariate logistic regression models.Results: AF was present in 8.5% of patients with 11.6% of AF patients having rheumatic heart disease (RHD) and 8.7% having other valvular diseases. With increasing age, the proportion of RHD-related AF decreased and the risk factors for non-valvular AF increased. There was a significantly higher proportion of risk factors for non-valvular AF in men than in women (p=0.008), but RHD-related AF was more prevalent in women than men (p=0.013). The patients with non-valvular AF had significantly higher BMI and EFV with more pronounced elevation of EFV (p< 0.001). Multivariate logistic regression showed a significant association of EFV with AF after adjustment for BMI and clinical risk factors, and the highest EFV quartile was associated with AF independent of left atrial size and obstructive coronary artery disease.Conclusion: The association of EFV with non-valvular AF in Chinese patients was independent of generalized adiposity and clinical risk factors especially in highest EFV quartile. These findings support the growing appreciation of the association of EFV with AF.Keywords: atrial fibrillation, epicardial fat, pericardial fat, obesity, body mass index, computed tomography, echocardiography

The Homeodomain leucine zipper (HD-Zip) transcription factor family is one of the most important transcription factor families in the plant kingdom and it plays pivotal roles in plant development, growth as well as response to all kinds of stresses. However, the HD-Zip gene family has not been characterized in pineapple yet. Pineapple is one of the most economically important tropical fruit in the world. Here, we identified a total of 33 HD-Zip genes in pineapple by a genome-wide study. These 33 genes were divided into 4 subgroups and variably located on 14 chromosomes and one scaffold_1724. The gene structure and conserved motifs of these genes relatively share similar characteristics in a subfamily. We found at least two abiotic stress responding cis-elements in the promoter region of AcoHDzip genes, the light-responsive element is the most abundant cis-element that can be found in all the genes. Besides, transcriptome analysis showed the expression profile of 33 genes in different developmental stages. We identified the nine genes with higher expression in gynoecium and two genes with highly expressed in ovules and flowers respectively. Our studies will provide valuable information about the HD-Zip transcription factor family in pineapple, which would be useful for further functional studies in plant growth, plant development, and stress response.

Combined antitumor therapies based on nanomedicines have shown efficacy in various tumor models in recent years, overcoming the disadvantages of inefficiency and undesired toxicity of traditional therapies. Herein, we present a copper sulfide- and doxorubicin-loaded gold nanorods@mesoporous SiO2 multifunctional nanocomposite (AuNR@mSiO2@DOX-CuxS-PEG) to integrate chemotherapy, the photothermal properties of AuNRs, and the photodynamic properties of CuxS into a single nanoplatform based on hydrophobic interaction and electrostatic attraction. Upon near-infrared light irradiation, the AuNR@mSiO2@DOX-CuxS-PEG nanocomposites exhibit a synergistic therapeutic effect and inhibit the in situ tumor growth and lung metastasis in a melanoma model. This occurs because of the high photothermal conversion efficiency, boosted intracellular reactive oxygen species production, and excellent doxorubicin (DOX) release, as well as an induced tumor-specific immune response. The inspired antitumor immunity was confirmed by elevated infiltration of activated T cells in tumor tissues and improved maturation and activation of dendritic cells in tumor-draining lymph nodes. This study highlights the superior antitumor therapeutic effect elicited by a multifunctional nanoplatform for skin with in situ melanoma and lung metastasis inhibition, indicating its satisfactory clinical application prospects.

Background Reduction in elevated serum cholesterol concentrations is important in the management of individuals at risk of atherosclerotic cardiovascular disease (ASCVD), such as myocardial infarction and thrombotic stroke. Although HMGCoA reductase inhibitors (“statins”) are frequently used for this purpose, a significant proportion of patients remain at increased residual risk of ASCVD as they do not adequately address some of the associated co-morbidities such as diabetes and fatty liver disease. Methods A double-blind, randomized, placebo-controlled, dose ranging study was carried out that compared three doses of berberine ursodeoxycholate (BUDCA) to placebo in a cohort of subjects with a history of hypercholesterolemia and serum LDL cholesterol levels above 2.59 mmol/L (> 99.9 mg/dL). BUDCA was administered in two divided doses each day for 28 days. The primary endpoints of the study were safety and tolerability of this new compound, as well as its effect in lowering serum lipid and lipoprotein concentrations. Results A total of 50 subjects were enrolled into three dose cohorts in this study. BUDCA was generally well tolerated, even at doses of 2000 mg per day (the highest dose group); there were no significant adverse effects reported and this highest dose was associated with significant reductions in LDL cholesterol. By day 28 and with the highest dose of BUDCA, there were significant reductions in the serum concentrations of total cholesterol by 8.2% (P = 0.0004) and LDL cholesterol by 10.4% (P = 0.0006), but no significant changes in triglyceride and HDL cholesterol concentrations. Conclusions BUDCA is a new single molecular entity that has a significant but modest effect in safely lowering serum LDL-cholesterol concentrations in individuals with a history of hypercholesterolemia. It has a potential use for treating hypercholesterolemia in individuals who cannot take statins, and possibly as adjunctive to other agents, such as ezetimibe or bempedoic acid. Trial registration The study was registered on Clinicaltrials.gov (NCT03381287).

BackgroundMedical complications strongly affected the mortality of patients with stroke. However, only limited research has studied the effect of in-hospital medical complications on the mortality of patients with spontaneous intracerebral haemorrhage (ICH) globally. Using the China National Stroke Registry, the effect was prospectively and systematically investigated in patients with spontaneous ICH during their hospitalisation, at 3, 6 and 12 months after disease onset.MethodsThis study collected data on patients over 18 years old with spontaneous ICH from 132 Chinese clinical centres across 32 provinces and four municipalities (Hong Kong included), from September 2007 to August 2008. Data on patient complications, death and other information were acquired through paper-based registry forms. Using multivariable logistic regression, the association of medical complications with stroke outcomes was evaluated.ResultsOf 3255 patients with spontaneous ICH, 878 (26.97%) had in-hospital medical complications. In-hospital medical complications were independent risk factors for death during the hospitalisation (adjusted OR 4.41, 95% CI 3.18 to 6.12), at 3 months (adjusted OR 2.18, 95% CI 1.70 to 2.80), 6 months (adjusted OR 1.84, 95% CI 1.45 to 2.34) and 12 months (adjusted OR 1.59, 95% CI 1.26 to 2.01) after spontaneous ICH.ConclusionThe results revealed that the short-term and long-term mortality of patients with spontaneous ICH in China was significantly associated with their in-hospital medical complications.

BackgroundWhether to treat minor stroke with intravenous tissue plasminogen activator (t-PA) treatment or antiplatelet therapy is a dilemma. Our study aimed to explore whether intravenous t-PA treatment, dual antiplatelet therapy (DAPT) and aspirin have different efficacies on outcomes in patients with minor stroke.MethodsA post hoc analysis of patients with acute minor stroke treated with intravenous t-PA within 4.5 hours from a nationwide multicentric electronic medical record and patients with acute minor stroke treated with DAPT and aspirin from the Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack Database. Minor stroke was defined by a score of 0–3 on the National Institutes of Health Stroke Scale at randomisation. Favourable functional outcome (defined as modified Rankin Scale (mRS) score of 0–1 or 0–2 at 3 months).ResultsCompared with those treated with intravenous t-PA, no significant association with 3-month favourable functional outcome (defined as mRS score of 0–1) was found neither in patients treated with aspirin (87.8% vs 89.4%; OR, 0.83; 95% CI, 0.46 to 1.50; p=0.53) nor those treated with DAPT (87.4% vs 89.4%; OR, 0.84; 95% CI, 0.46 to 1.52; p=0.56). Similar results were observed for the favourable functional outcome defined as mRS score of 0–2 at 3 months.ConclusionsIn our study, no significant advantage of intravenous t-PA over DAPT or aspirin was found. Due to insufficient sample size, our study is probably unable to draw such a conclusion that that intravenous t-PA was superior or non-superior to DAPT.

Quantitative real-time PCR (qRT-PCR) is a convenient tool for gene expression analysis. However, reliability of its result is influenced largely by the selection of reference genes. Pineapple molecular breeding is limited due to lack of understanding of sexual organs’ development. Similarly, only a few reference genes have identified for qRT-PCR analysis in pineapple stamen and ovule. In this study, we initially identified 20 candidate reference genes using transcriptome data, and determined their expression stabilities in 36 ovule and stamen developmental samples using qRT-PCR. Three algorithms, GeNorm, NormFinder, and BestKeeper were used to determine the superiority of those candidate genes. Our results revealed that the use of combined RPS4 and RPL23 during ovule development, CCR and RPS4 during stamen development were sufficient for reliable normalization. These recommended reference genes were further verified by evaluating the temporal expression abundance of the meiosis-specific protein-encoding genes AcASY1 and AcASY3 in all experimental samples. Our results complement previous pineapple normalization study by providing appropriate reference genes during the entire reproductive period, and will beneficial for future studies on the pineapple stamen and ovule development. Finally, this result will help for the molecular breeding of pineapple for crop improvement.

Fibroblast growth factor receptor type 2 (FGFR2) has emerged as a key oncogenic factor that regulates gastric cancer (GC) progression, but the underlying mechanism of FGF–FGFR2 signaling pathway remains largely unknown. To identify the potential molecular mechanisms of the oncogenic FGFR2 in gastric carcinogenesis and convey a novel therapeutic strategy, we profiled the FGFR alterations and analyzed their clinical associations in TCGA and Hong Kong GC cohorts. We found that FGFR2 overexpression in GC cell lines and primary tumors predicted poor survival and was associated with advanced stages of GC. Functionally, growth abilities and cell cycle progression of GC were inhibited by inactivation of ERK–MAPK signal transduction after FGFR2 knockdown, while apoptosis was promoted. Meanwhile, the first-line anti-cancer drug sensitivity was enhanced. RNA-seq analysis further revealed that YAP1 signaling serves as a significant downstream modulator and mediates the oncogenic signaling of FGFR2. When stimulating FGFR2 by rhFGF18, we observed intensified F-actin, nuclear accumulation of YAP1, and overexpression of YAP1 targets, but these effects were attenuated by either FGFR2 depletion or AZD4547 administration. Additionally, the FGF18–FGFR2 signaling upregulated YAP1 expression through activating c-Jun, an effector of MAPK signaling. In our cohort, 28.94% of GC cases were characterized as FGFR2, c-Jun, and YAP1 co-positive and demonstrated worse clinical outcomes. Remarkably, we also found that co-targeting FGFR2 and YAP1 by AZD4547 and Verteporfin synergistically enhanced the antitumor effects in vitro and in vivo. In conclusion, we have identified the oncogenic FGF–FGFR2 regulates YAP1 signaling in GC. The findings also highlight the translational potential of FGFR2–c-Jun–YAP1 axis, which may serve as a prognostic biomarker and therapeutic target for GC.

Chemotherapy-induced alopecia is a common and emotionally traumatic side effect on breast cancer patients. In order to make up for the deficiency of measuring tools in China, our study aims at translating the chemotherapy-induced alopecia distress scale (CADS) into Chinese and evaluating the psychometric properties of the Chinese version of CADS (CADS-C) in breast cancer patients. The validity and reliability of CADS-C were measured by a questionnaire survey among 301 breast cancer patients from Chinese mainland. Construct validity was assessed through factor analysis and contrasted group comparisons. The validity of the content was examined by an experts group. The internal consistency and test–retest reliability were evaluated by calculating Cronbach’s alpha and the intraclass correlation coefficient. The content validity index was 0.94; a structure with three factors was revealed by exploratory factor analysis which explained 65.40% of the variance and proved by confirmatory factor analysis. The contrasted group comparisons showed significant differences among different degrees of alopecia. The average variance extracted and composite reliability and correlations between CADS and body image, quality of life and self-esteem proved the convergent validity. The Cronbach’s alpha and the intraclass correlation coefficient of the total scale were 0.90 and 0.89 respectively, indicating satisfactory internal consistency and time stability. The scale appears to be a reliable and valid tool to measure chemotherapy-induced alopecia distress among breast cancer patients in China.

Stress is associated with an increased risk of hypertension, and the incidence of stress-related hypertension has risen rapidly in recent years; however, the underlying mechanisms remain elusive. Gut dysbiosis has been demonstrated to contribute to hypertension and hyperactivation of the hypothalamus-pituitary-adrenal (HPA) axis. Based on our previous findings showing the altered gut microbiota in the rats of stress-induced hypertension (SIH), the present study aims to investigate whether the stress-induced alteration in gut microbiota can lead to the dysfunction of the HPA axis which contributes to the development of SIH. SIH was developed in rats subjected to electric foot-shock combined with buzzer noise stressors. The gut microbiota of rats were deleted by administering an antibiotic cocktail containing ampicillin (1 g/L), vancomycin (500 mg/L), neomycin (1 g/L), and metronidazole (1 g/L) in drinking water. The serum levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were tested using enzyme-linked immunosorbent assay (ELISA). The mRNA expression of glucocorticoid receptor (GR) and corticotropin-releasing factor (CRF), CRFR1 and CRFR2 was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The cellular protein expressions of corticotropin-releasing hormone (CRH), c-fos, and GR were examined by immunohistochemical staining. In the present study, SIH rats showed a hyperactive HPA axis as indicated by the increased CRH expression in the paraventricular nucleus (PVN) of the hypothalamus, the elevated serum ACTH or CORT concentrations, and increased adrenal gland index. The decreased GR expression and increased CRFR1 in the hypothalamus might underlie the hyperactivation of the HPA axis. The microbial deletion by antibiotics mitigated the hyperactivation of the HPA axis and attenuated the stress-induced elevation of blood pressure, indicating that the causal link of gut microbiota to SIH is mediated, at least in part, by the HPA axis activity. Our findings shed new light on the mechanisms underlying SIH.

During the COVID-19 epidemic, the treatment of critically ill patients has been increasingly difficult and challenging. During the epidemic, some patients with neurological diseases also have COVID-19, which could be misdiagnosed and cause silent transmission and nosocomial infection. Such risk is high in a neurological intensive care unit (NCU). Therefore, prevention and control of epidemic in critically ill patients is of utmost importance. The principle of NCU care should include comprehensive screening and risk assessment, weighing risk against benefits and reducing the risk of COVID-19 transmission while treating patients as promptly as possible.

Many flatfish species, such as Scophthalmus maximus, Paralichthys olivaceus, Solea senegalensis, are extensively cultured worldwide. In flatfishes, eye migration varies among different species and even within the same species. The genetic mechanism underlying eye migration is still unclear, and it is the key to improve metamorphosis in flatfish aquaculture and understand flatfish evolution. In this study, the high frequency of eye location variants in an artificial S. senegalensis population allowed us to investigate the eye preference during migration; completeness of the eye migration; and other related left-right asymmetric characteristics, such as asymmetrical skull remodeling and lying down on one side. The different frequencies of eye preference during migration, completeness of the eye migration, and settling side suggest that they are determined by different genotypes and imply independent evolutionary events during flatfish evolution. We found that the swimming time may be related to the completeness of eye migration, and further the migration of the eye, the more time the fish spent at the sea bottom. The left-right asymmetric degrees of not only the frontal bones and lateral ethmoids but also the jaw bone, including the premaxillary, maxillary, and dentary bones, depend on the completeness of eye migration. Finally, we proposed a hypothesis for the asymmetric origin of flatfish that provides reasonable explanations for the selective advantages of primitive flatfish species.

Antimicrobial peptides (AMPs) are an important part of the human innate immune system for protection against bacterial infections, however the AMPs display varying degrees of activity against Staphylococcus aureus. Previously, we showed that inactivation of the ATP synthase sensitizes S. aureus towards the AMP antibiotic class of polymyxins. Here we wondered if the ATP synthase similarly is needed for tolerance towards various human AMPs, including human β-defensins (hBD1-4), LL-37 and histatin 5. Importantly, we find that the ATP synthase mutant (atpA) is more susceptible to killing by hBD4, hBD2, LL-37 and histatin 5 than wild type cells, while no changes in susceptibility was detected for hBD3 and hBD1. Administration of the ATP synthase inhibitor, resveratrol, sensitizes S. aureus towards hBD4-mediated killing. Neutrophils rely on AMPs and reactive oxygen molecules to eliminate bacteria and the atpA mutant is more susceptible to killing by neutrophils than the WT, even when the oxidative burst is inhibited.These results show that the staphylococcal ATP synthase enhance tolerance of S. aureus towards some human AMPs and this indicates that inhibition of the ATP synthase may be explored as a new therapeutic strategy that sensitizes S. aureus to naturally occurring AMPs of the innate immune system.

This study aims to evaluate the effects of prolonged expressive writing on health outcomes in breast cancer patients undergoing chemotherapy to help understand how the dosage of an expressive writing intervention might moderate its effects. A total of 112 breast cancer patients undergoing chemotherapy were randomly allocated to the expressive writing group (n = 56) or the prolonged expressive writing group (n = 56). The expressive writing group received the standard expressive writing intervention based on Pennebaker’s prompt to write for at least 20 min over four consecutive days (4 sessions). The prolonged expressive writing group used a modified prompt: write for at least 20 min 3 times a week over a 4-week period (12 sessions); patients could choose whether to write on consecutive days or not. All participants were required to write about their stressor-related upsetting or traumatic feelings about breast cancer. Outcomes were assessed and compared at baseline, as well as 1 month, 3 months, and 6 months postintervention. There was no significant difference in the patients’ quality of life, or physical and psychological wellbeing between the expressive writing group and the prolonged expressive writing group at any time point (all p > .05). The quality of life of breast cancer patients significantly decreased in the two groups over time (F = 40.64, p

Stroke is the third leading cause of long-term disability. Effective stroke rehabilitation should be provided to patients with a moderate or severe stroke so as to achieve functional recovery. Also, stroke rehabilitation is moving towards more intense therapy models that incorporate technologies such as robotics and computer games. Evidence-based guidelines are useful for promoting the best possible clinical practices. This guideline summarises the modes of stroke rehabilitation in China—three-stage rehabilitation network, rehabilitation of stroke dysfunction, training for activities of daily living, stroke complications and rehabilitation care. The aim of this guideline was to provide a synopsis of best clinical practices in the stroke rehabilitation of adult patients in China.

Previous studies suggested that serine can promote the synthesis of selenoproteins and the interaction, transformation, and replacement of serine, cysteine, and selenocysteine have been observed in the human body. This study was designed to clarify whether the dietary intakes of serine and sulfate-containing amino acids (SAAs) could directly affect the selenium (Se) nutritional status or the level of milk Se in lactating women. Breast milk and plasma samples were collected from a total of 264 lactating Chinese women when they revisited their local hospital at the 42nd day postpartum to detect the concentration of Se with ICP-MS and the content of selenoprotein P (SEPP1) and the activity of glutathione peroxidase 3 (GPX3) in the plasma by ELISA. The daily Se intake by each subject was calculated based on her own plasma Se concentration. The 24-h dietary record data for 3 consecutive days were collected to calculate their dietary intakes of protein together with each amino acid daily based on the China Food Composition Tables (CFCT). Ordinal polytomous logistic regression was applied to examine the determinants of BMI values for lactating women. For all subjects, the concentration of plasma SEPP1 and milk Se of participants with insufficient Se intake were significantly associated with the dietary intake of serine and 2 SAAs (methionine and cystine), respectively (P 0.05). No significant correlation was found between each amino acid related to the synthesis of endogenous serine and every biomarker of the Se nutrition status in subjects with an insufficient dietary protein intake (P 0.05). The ordinal logistic regression analysis showed that dietary protein intake (ordinal OR 1.012, 95% CI = 0.004-0.020, P = 0.002) and plasma SEPP1 (ordinal OR 0.988, 95% CI = - 0.023 to - 0.001, P = 0.036) affected the BMI value together in these lactating women. In conclusion, dietary serine and SAAs were found to directly affect the nutritional status, and both high protein intake and low plasma SEPP1 might be the health risks in these lactating Chinese women.

AimStroke is the leading cause of disability and death in China. Ischaemic stroke accounts for about 60%–80% of all strokes. It is of considerable significance to carry out multidimensional management of ischaemic cerebrovascular diseases. This evidence-based guideline aims to provide the latest detailed and comprehensive recommendations on the diagnosis, treatment and secondary prevention of ischaemic cerebrovascular diseases.MethodsWe had performed comprehensive searches of MEDLINE (via PubMed) (before 30 June 2019), and integrated the relevant information into charts and distributed to the writing group. Writing group members discussed and determined the recommendations through teleconference. We used the level of evidence grading algorithm of Chinese Stroke Association to grade each recommendation. The draft was reviewed by the Guideline Writing Committee of Chinese Stroke Association Stroke and finalised. This guideline is fully updated every 3 years.ResultsThis evidence-based guideline is based on the treatment, care and prevention of ischaemic cerebrovascular diseases, which emphasises on pathogenesis evaluation, intravenous thrombolysis, endovascular therapy, antiplatelet therapy, prevention and treatment of complications, and risk factor management.ConclusionsThis updated guideline presents a framework for the management of ischaemic cerebrovascular diseases. Timely first-aid measures, professional care in the acute stage, and proactive secondary prevention will be helpful to patients.

NLRP3 (NOD-, LRR- and pyrin domain- containing protein 3) inflammasome is involved in diverse inflammatory diseases, so the activation of NLRP3 inflammasome needs to be tightly regulated to prevent excessive inflammation. However, the endogenous regulatory mechanisms of NLRP3 inflammasome are still less defined. Here, we report that β-catenin, which is the central mediator of the canonical Wnt/β-catenin signaling, promotes NLRP3 inflammasome activation. When we suppressed the expression of β-catenin by siRNA or pharmacological inhibitor, the NLRP3 inflammasome activation was impaired. Accordingly, β-catenin inhibitor attenuated LPS-induced systemic inflammation in vivo. Mechanistically, we found β-catenin interacted with NLRP3 and promoted the association between NLRP3 and ASC. Thus, our study revealed a novel role of β-catenin in NLRP3 inflammasome activation and suggest an endogenous crosstalk between Wnt/β-catenin signal and NLRP3 inflammasome.

BackgroundThe effect of cerebral small vessel disease (CSVD) and intracranial arterial stenosis (ICAS) on stroke outcomes remains unclear.MethodsData of 1045 patients with minor stroke or transient ischaemic attack (TIA) were obtained from 45 sites of the Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial. We assessed the associations of burdens of CSVD and ICAS with new strokes and bleeding events using multivariate Cox regression models and those with modified Rankin Scale (mRS) scores using ordinal logistic regression models.ResultsAmong the 1045 patients, CSVD was present in 830 cases (79.4%) and ICAS in 460 (44.0%). Patients with >1 ICAS segment showed the highest risk of new strokes (HR 2.03, 95% CI 1.15 to 3.56, p=0.01). No association between CSVD and the occurrence of new strokes was found. The presence of severe CSVD (common OR (cOR) 2.01, 95% CI 1.40 to 2.89, p1 ICAS segment (cOR 2.15, 95% CI 1.57 to 2.93, pInterpretationCSVD is associated with more disability and bleeding events, and ICAS is associated with an increased risk of stroke and disability in patients with minor stroke and TIA at 3 months. CSVD and ICAS may represent different vascular pathologies and play distinct roles in stroke outcomes.Trial registration numberNCT00979589

Background S100A8/A9 is implicated in inflammation mechanisms related to atherosclerosis and plaque vulnerability, but it remains unclear whether S100A8/A9 is associated with the prognosis of ischemic stroke. The aim of this study was to investigate these associations in 2 independent multicenter cohorts. Methods Plasma S100A8/A9 concentrations at baseline were measured among 4785 patients with ischemic stroke from 2 independent cohorts: Infectious Factors, Inflammatory Markers, and Prognosis of Acute Ischemic Stroke (IIPAIS) and China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was a composite outcome of death or major disability at 3 months after ischemic stroke. Secondary outcomes were major disability, death, and a composite outcome of death or vascular events. Results Among the combined participants of IIPAIS and CATIS, the adjusted odds ratios associated with the highest quartile of plasma S100A8/A9 were 2.11 (95% CI, 1.66–2.68) for the primary outcome and 1.62 (95% CI, 1.27–2.07) for the secondary outcome of major disability; adjusted hazard ratios were 4.14 (95% CI, 2.10–8.15) for the secondary outcome of death and 2.08 (95% CI, 1.38–3.13) for the composite outcome of death or vascular events. Each SD increase of log-transformed S100A8/A9 was associated with 28% (95% CI, 18%–39%; P Conclusions High plasma S100A8/A9 concentrations at baseline were independently associated with increased risks of adverse clinical outcomes at 3 months after ischemic stroke, suggesting that S100A8/A9 might have a role as a prognostic marker of ischemic stroke.

ObjectiveGastrointestinal (GI) bleeding in patients who had a stroke is strongly associated with a higher risk of death and loss of independence. However, it is unknown whether GI bleeding increases risk for recurrence of stroke. In this study, we assess the potential relationship between GI bleeding and stroke recurrence in patients within 12 months of an acute ischaemic stroke (AIS), using the China National Stroke Registry (CNSR).MethodsThis study included 22 216 patients who had an ischaemic stroke included in the CNSR from 2007 to 2008. We analysed baseline patient characteristics, GI bleeding and outcomes of patients who had an AIS, specifically stroke recurrence at 3, 6 and 12 months. We used multivariable logistic regression to evaluate a possible association between GI bleeding and stroke recurrence.ResultsOf the 12 415 patients included in our study, 12.3%, 15.5% and 17.7% had a stroke recurrence at 3, 6 and 12 months, respectively. GI bleeding was an independent stroke recurrence risk factor in patients after ischaemic stroke at 3 months (adjusted OR 1.481, 95% CI 1.118 to 1.962), 6 months (adjusted OR 1.448, 95% CI 1.106 to 1.896) and 12 months (adjusted OR 1.350; 95% CI 1.034 to 1.763).ConclusionGI bleeding was associated with the increased risk of stroke recurrence after an AIS.

Hippo signaling functions to limit cellular growth, but the aberrant nuclear accumulation of its downstream YAP1 leads to carcinogenesis. YAP1/TEAD complex activates the oncogenic downstream transcription, such as CTGF and c-Myc. How YAP1 is protected in the cytoplasm from ubiquitin-mediated degradation remains elusive. In this study, a member of Angiomotin (Motin) family, AMOTL1 (Angiomotin Like 1), was screened out as the only one to promote YAP1 nuclear accumulation by several clinical cohorts, which was further confirmed by the cellular functional assays. The interaction between YAP1 and AMOTL1 was suggested by co-immunoprecipitation and immunofluorescent staining. The clinical significance of the AMOTL1–YAP1–CTGF axis in gastric cancer (GC) was analyzed by multiple clinical cohorts. Moreover, the therapeutic effect of targeting the oncogenic axis was appraised by drug-sensitivity tests and xenograft-formation assays. The upregulation of AMOTL1 is associated with unfavorable clinical outcomes of GC, and knocking down AMOTL1 impairs its oncogenic properties. The cytoplasmic interaction between AMOTL1 and YAP1 protects each other from ubiquitin-mediated degradation. AMOTL1 promotes YAP1 translocation into the nuclei to activate the downstream expression, such as CTGF. Knocking down AMOTL1, YAP1, and CTGF enhances the therapeutic efficacies of the first-line anticancer drugs. Taken together, AMOTL1 plays an oncogenic role in gastric carcinogenesis through interacting with YAP1 and promoting its nuclear accumulation. A combination of AMOTL1, YAP1, and CTGF expression might serve as a surrogate of Hippo activation status. The co-activation of the AMOTL1/YAP1–CTGF axis is associated with poor clinical outcomes of GC patients, and targeting this oncogenic axis may enhance the chemotherapeutic effects.

GILZ expression is induced by glucocorticoids (GCs) and is involved in the mechanism of airway epithelial cell repair in patients with asthma. The present study aimed to investigate the role of miR-222-3p/GILZ pathway in treatment of airway epithelial cell repair by GCs. 9HTE cells were treated by 10 µmol/L dexamethasone (Dex) for 6, 12, and 24 hours (h). MiR-222-3p mimic and GILZ were used for cell transfection. Cell vitality, migration, and invasion were detected by methyl-thiazolyl tetrazolium (MTT), wound healing, and Transwell. The targeting relationship between miR-222-3p and GILZ was predicted by TargetScan and further confirmed by dual-luciferase reporter assay. The expressions of relative mRNAs or proteins were detected by Western blot and quantitative polymerase chain reaction (qPCR). The results showed that Dex treatment up-regulated the GILZ expression level but inhibited the levels of p-Raf1, p-MEK1/2, p-ERK1/2, and miR-222-3p of the cells, moreover, it also inhibited cell activity, migration, and invasion in a time-dependent manner. MiR-222-3p specifically targeted GILZ. MiR-222-3p mimic ameliorated the cell viability, migration, and invasion reduced by Dex treatment, increased the expression levels of p-Raf1 and p-MEK1/2, p-ERK1/2, and partially reversed the effects of GILZ overexpression on the above indexes. Moreover, GILZ showed the opposite effects to miR-222-3p. MiR-222-3p activated MAPK signaling pathway through inhibiting the GILZ expression, thus promoting the cell viability, migration, and invasion previously reduced by Dex.

Purpose: Hesperidin has anti-inflammatory and anti-oxidant stress effects, but its functions in chronic obstructive pulmonary disease (COPD) remains unknown. This study analyzed the role of hesperidin in COPD mice, aiming to provide a basis for the hesperidin application.Materials and methods: Mice were injected with cigarette smoke extract (CSE) to construct COPD models and then treated with budesonide or hesperidin. Hematoxylin-eosin (HE) and TUNEL assays were used to observe the pathological changes and cell death of lung tissue. The levels of interleukin (IL)-6, IL-8, malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) in bronchoalveolar lavage fluid (BLAF), as well as myeloperoxidase (MPO) content in lung tissues were confirmed. The expression levels of SIRT1, PGC-1α, and p65 proteins were measured by western blotting (WB) analysis.Results: CSE induced inflammatory cell infiltration and cell death in the lung tissues of mice, whereas budesonide and hesperidin effectively alleviated these pathological changes. The levels of IL-6, IL-8, and MDA in BLAF and pulmonary MPO content in the COPD mice were effectively increased, while the levels of SOD and CAT in BLAF were decreased, which could be reversed by budesonide and hesperidin. Moreover, the addition of budesonide or hesperidin reliably accelerated the expression levels of PGC-1α and SIRT1 but suppressed the phosphorylation of p65 in COPD mice. In general, high-dose hesperidin had a stronger regulatory effect on COPD mice.Conclusions: Hesperidin alleviated inflammation and oxidative stress responses in CES-induced COPD mice, associated with SIRT1/PGC-1α/NF-κB signaling axis, which might become a new direction for COPD treatment.

Liver cancer stem cells (LCSCs) initiate hepatocellular carcinoma (HCC) and contribute to its recurrence and treatment resistance. Studies have suggested ZBP-89 as a candidate tumor suppressor in HCC. We explored the role of ZBP-89 in the regulation of LCSCs. This study was performed in liver tissue samples from 104 HCC patients, 2 cell lines and mouse tumor models. We demonstrated that ZBP-89 was weakly expressed in LCSCs. Patients with high expression of LCSC markers displayed reduced survivals and higher recurrence rates after curative surgical operation. The expression of ZBP-89 was predictive for decreased recurrence. LCSC markers were negatively correlated with ZBP-89 in HCC tissues and in enriched liver tumor spheres. The exogenous expression of ZBP-89 attenuated the tumor-sphere formation and secondary colony formation capabilities of LCSCs in vitro and tumorigenicity in vivo. Furthermore, the negative effect of ZBP-89 on cancer stemness was Notch1-dependent. Localized with Notch1 intracellular domain (NICD1) in the nucleus, ZBP-89 repressed the Notch1 signaling pathway by competitive binding to NICD1 with MAML1. Collectively, ZBP-89 negatively regulates HCC stemness via inhibiting the Notch1 signaling.

Angiosperm reproductive development is a complex event that includes floral organ development, male and female gametophyte formation and interaction between the male and female reproductive organs for successful fertilization. Previous studies have revealed the redundant function of ATP binding cassette subfamily G (ABCG) transporters ABCG1 and ABCG16 in pollen development, but whether they are involved in other reproductive processes is unknown. Here we show that ABCG1 and ABCG16 were not only expressed in anthers and stamen filaments but also enriched in pistil tissues, including the stigma, style, transmitting tract and ovule. We further demonstrated that pistil-expressed ABCG1 and ABCG16 promoted rapid pollen tube growth through their effects on auxin distribution and auxin flow in the pistil. Moreover, disrupted auxin homeostasis in stamen filaments was associated with defective filament elongation. Our work reveals the key functions of ABCG1 and ABCG16 in reproductive development and provides clues for identifying ABCG1 and ABCG16 substrates in Arabidopsis.

We studied the genetic diversity of 34 fig varieties (Ficus carica L.) to provide a reference for analyzing the phylogenetic relationships and variety identification of figs. A total of 34 fig materials were amplified by inter-simple sequence repeat (ISSR) molecular marker technique. The products were detected by agarose gel electrophoresis and analyzed by using POPGENE 1.32 and NTSYS 2.10. Nine polymorphic primers were screened from 100 ISSR primers, and 107 loci were amplified, 74 were polymorphic loci, and the polymorphic loci ratio was 69.16%. The number of alleles was observed. The Na average was 1.6729, and the effective allele number (Ne) was 1.4022. The Nei’s gene diversity index (He) was 0.2316. The Shannon information index (I) was 0.3447, and the genetic similarity coefficient (GS) was between 0.6262 and 0.9720 the average values. UPGMA method was used to construct the clustering map. With GS 0.824 as the threshold, 34 fig varieties were divided into eight groups, thus indicating that ISSR molecular markers can be effectively applied to the genetic diversity analysis of different fig varieties.

Ependymomas are primary glial tumors arising from cells related to the ependymal lining of the ventricular system. They are classified into at least nine different molecular subtypes according to molecular phenotype, histological morphology, and tumor location. Primary sellar ependymoma is an extremely rare malignancy of the central nervous system, with only 12 known cases reported in humans. We herein report a case of ependymoma located at the pituitary region in a 44-year-old female patient and discuss the molecular subtype, natural history, clinical presentation, radiological findings, histological features, immunohistochemical characteristics, ultrastructural examinations, treatment, and prognosis of sellar ependymoma. This case report may serve as a helpful reference for clinicians and radiologists in clinical practice.

Accumulating evidences have revealed the dysregulated expressions and critical roles of non-coding RNAs in various malignancies, including cervical cancer. Nevertheless, our knowledge about the vast majority of non-coding RNAs is still lacking. Here we identified long non-coding RNA (lncRNA) SPINT1-AS1 as a novel cervical cancer-associated lncRNA. SPINT1-AS1 was increased in cervical cancer and correlated with advanced stage and poor prognosis. SPINT1-AS1 was a direct downstream target of miR-214, a well-known tumor suppressive microRNA (miRNA) in cervical cancer. Intriguingly, SPINT1-AS1 was also found to repress miR-214 biogenesis via binding DNM3OS, the primary transcript of miR-214. The interaction between SPINT1-AS1 and DNM3OS repressed the binding of DROSHA and DGCR8 to DNM3OS, blocked DNM3OS cleavage, and therefore repressed mature miR-214 biogenesis. The expression of SPINT1-AS1 was significantly negatively correlated with miR-214 in cervical cancer tissues, supporting the reciprocal repression between SPINT1-AS1 and miR-214 in vivo. Through downregulating mature miR-214 level, SPINT1-AS1 upregulated the expression of β-catenin, a target of miR-214. Thus, SPINT1-AS1 further activated Wnt/β-catenin signaling in cervical cancer. Functionally, SPINT1-AS1 drove cervical cancer cellular proliferation, migration, and invasion in vitro, and also tumorigenesis in vivo. Deletion of the region mediating the interaction between SPINT1-AS1 and DNM3OS, overexpression of miR-214, and inhibition of Wnt/β-catenin signaling all reversed the roles of SPINT1-AS1 in cervical cancer. Collectively, these findings identified SPINT1-AS1 as a novel cervical cancer-associated oncogenic lncRNA which represses miR-214 biogenesis and activates Wnt/β-catenin signaling, highlighting its potential as prognostic biomarker and therapeutic target for cervical cancer.

Intracranial atherosclerotic stenosis (ICAS) is one of most common causes of stroke; it has the highest rate of recurrence compared with other aetiologies.1 ICAS is especially more prevalent among the Asians.2 The results of the Chinese Intracranial Atherosclerosis Study indicated that the prevalence of symptomatic ICAS (sICAS) is as high as 46%.1 The 1-year stroke recurrence rate with sICAS is reported to be 12.2% and 15%.3 4 We understand, the following pathological reasons could account for the high recurrence rate in sICAS. First, patients with ICAS are prone to encounter hypoperfusion haemodynamics, especially under poor collateral conditions.5 Studies on the association of blood pressure (BP) control in the acute stage and clinical outcomes are contradictory, supporting this hypothesis.6 Second, plaques in stenotic arteries are usually highly vulnerable (due to large lipid cores, thin fibrous caps and intraplaque haemorrhage).7 These plaques are prone to rupture into downstream arteries, leading to embolic stroke in the territory of the responsible artery.5 Furthermore, these patients are often comorbid with heightened risk factors strongly correlated with stroke recurrence, including hypertension, metabolic disorders, dyslipidaemia.8 Therefore, there is an urgent need to standardise assessment and management of sICAS. The treatment of sICAS nowadays primarily focuses on secondary prevention to reduce stroke recurrence. Therapeutic methods include antiplatelet therapy, interventional therapy and control of risk factors.9 Two milestone trials, the Warfarin Aspirin Symptomatic Intracranial Disease (WASID)3 Trial and the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS)4 Trial aim to provide an updated strategy for clinical practice. The WASID Trial, with a double-blind, multicentre, randomised control clinical trial design, aimed to evaluate the efficacy and safety of warfarin over aspirin among patients with 50%–99% degree of ICAS. Aspirin proved to be equally efficient …

Background: Genetic alteration profile of epidermal growth factor receptor ( EGFR ) mutant resected non- small cell lung cancer (NSCLC) and its relationship with clinical outcomes remains to be illustrated and genetic biomarkers that can predict recurrence need to be figured out. Methods: Clinicopathological and follow-up information were collected for 99 EGFR -mutant resected NSCLC. Tumor sections were collected for genetic alteration detection. Targeted next-generation sequencing (NGS) was performed to detect somatic mutations within each sample using a 285-gene panel on the Ion Torrent platform. Results: Concurrent driver gene mutations were detected in 86 participants. Adjuvant therapy was a positive factor in disease-free survival (DFS) period, and patients receiving tyrosine kinase inhibitors (TKIs) gained the longest DFS. A total of 34 concurrent mutant driver genes were found. The median number of mutated driver genes for each sample was 2 (range, 0–12). TP53 and NOTCH1 were the most frequent concurrent mutant driver genes with rates of 53.54% and 25.25% respectively. The number of concurrent mutant genes did not have a significant effect on recurrence. Multivariable analysis found that mutations of ATM (P=0.021), KIT (P=0.002), FGFR2 (P MET (P=0.015), PDGFRA (P=0.042), RB1 (P=0.006), and wildtype NOTCH1 (P=0.032), ERBB4 (P=0.012), FGFR3 (P=0.035) were independent risk factors for the recurrence of resected EGFR mutant NSCLC. Conclusions: TP53 and NOTCH1 was the most common concurrent mutant driver gene. Mutations of ATM, KIT, FGFR2, MET, PDGFRA, RB1 , and wildtype NOTCH1, ERBB4, FGFR3 were independent risk factors for the recurrence of resected EGFR mutant NSCLC.

Mycobacterium tuberculosis, the pathogen of tuberculosis (TB), can survive in host macrophages and induce macrophages to M2 phenotype might result in latent MTB infection. During the latent phase, the expression of MTB heat-shock protein 16.3 (Hsp16.3) is markedly increased among most of bacterial proteins, but the role of Hsp16.3 in macrophage M2 polarization is not clear. In this work, we found that macrophages incubated with 100 ng/ml MTB Hsp16.3 increased the production of Arg-1, IL-10, TGF-beta, and CD206. These results showed that MTB Hsp16.3 may induce macrophage M2 phenotype. And the interaction of Hsp16.3 with macrophages was found to depend on chemokine receptors CCRL2 and CX3CR1. Additionally, we used overexpression and silencing techniques to further verify the effect of CCRL2 and CX3CR1 on MTB Hsp16.3-induced M2 polarization macrophages. Furthermore, we explored the downstream signaling molecules of CCRL2 and CX3CR1 and we found MTB Hsp16.3 altered the signal transduction of the AKT/ERK/p38-MAPK. Taken together, this study provides evidence that MTB Hsp16.3 promotes macrophages to M2 phenotype and explores its underlying mechanism.

Myocardial infarction with nonobstructive coronary arteries (MINOCA) is a potentially multipathogenic syndrome that affects a subgroup of patients who present with acute myocardial infarction yet have no significant coronary artery disease on angiography. We herein describe a 71-year-old man with typical angina who showed inferior ST-segment elevation on electrocardiography and an increased troponin-I level. Emergency coronary angiography showed no angiographic stenosis. Cardiac magnetic resonance imaging (CMR) and myocardial contrast echocardiography (MCE) with two-dimensional speckle tracking imaging (2D-STI) were performed after coronary angiography. Good consistency was observed between the CMR findings and MCE with 2D-STI findings in identifying the potential causes of MINOCA. We explored an imaging method that is potentially more effective and accurate than CMR, namely MCE combined with 2D-STI, to identify myocardial abnormalities when angiography reveals no obstruction. This application of MCE with 2D-STI may optimize timely treatment. MINOCA has various causes, and the patient in this case was discharged with aspirin, verapamil, and atorvastatin on the presumption that the infarct had arisen from either plaque disruption or coronary spasm. In this study, we analyzed the etiology, clinical diagnosis, and treatment of MINOCA with reference to the relevant literature.

Public trust in medical profession has declined in the past decades. The deluge of health information available in various sources may be one contributing factor. However, how the health information acquisition influences patient trust remains unclear. With a general basis of Longo's Health Information Model, we proposed and tested mediation pathways linking three types of health information acquisition behaviors (scanning, seeking, and discussing) to patient trust in physicians, mediated by patient-centered communication. By using two iterations of probability sample surveys conducted in 2012 (

PURPOSE To investigate the activity and safety of daratumumab added to standard of care and evaluate the relative efficacy of DRd vs DVMP and other regimens on survival endpoints for untreated myeloma, we undertook this meta-analysis. METHODS We searched published reports that described the activity and safety of daratumumab added to standard of care for untreated myeloma. RESULTS Six daratumumab trials were identified, covering 5106 subjects. Daratumumab containing combinations for untreated myeloma attained an impressive complete response or better (≥CR) rate of 24%, very good partial response or better (≥VGPR) rate of 67%, overall response rate (ORR) of 92%. Daratumumab added to standard of care significantly improved progression free survival (PFS): the HR for PFS was 0.52 [0.44, 0.61], P

Background This paper reports the case of a giant saddle area lymphoid epithelial carcinoma as reference for clinical diagnosis and treatment. The clinical data of 1 patient who suffered from giant saddle area lymphoid epithelial carcinoma that invaded the bilateral cavernous sinus and surrounding internal carotid artery, slope, nasopharynx, oropharynx, sphenoid sinus, and ethmoid sinus were retrospectively analyzed. The treatment process and relevant literature were summarized. Case Description The 68-year-old man was admitted to the hospital because of headache and dizziness for one half a year and aggravation of visual deterioration for 2 months. Magnetic resonance imaging showed a large mass in the saddle area, about 8.11 × 8.12 × 6.2 cm in size. Successful removal of the saddle mass was achieved under transnasal endoscopic approach, and postoperative pathology indicated lymphoid epithelial carcinoma. Visual acuity improved, and the patient recovered well after the operation. Conclusions Giant saddle area lymphoid epithelial carcinoma is rare. Surgical removal should be selected as the initial treatment, and postoperative radiotherapy is indispensable for lymphoid epithelial carcinoma of the skull base and sinus.

In innate immune cells, pathogens and danger signals activate TLRs, unleashing potent and tailored inflammatory responses. Previously, we reported that an immune-specific transmembrane adaptor, SLP adaptor and CSK interacting membrane protein (SCIMP), interacts with TLR4 via direct binding to its cytoplasmic TIR domain. SCIMP scaffolds a Src family kinase, Lyn, for TLR4 phosphorylation and activation. Consequently, SCIMP is able to direct selective production of the proinflammatory cytokines IL-6 and IL-12p40 downstream of TLR4 in macrophages. Here, we set out to investigate whether SCIMP also acts as an adaptor for other TLR family members. We report here that SCIMP is phosphorylated and activated in response to agonists of multiple TLRs, including TLR2, TLR3, TLR4, and TLR9. SCIMP also interacts with TLRs that are known to signal from both the cell surface and endosomal compartments. In so doing, this transmembrane adaptor presents Lyn, along with other effectors such as Grb2, Csk, and SLP65, to multiple TLRs during cellular activation. CRISPR-mediated knockout or silencing of SCIMP in macrophages alters TLR signaling outputs and the production of IL-6 and IL-12p40 downstream of multiple TLRs, and upon challenge with live bacteria. Furthermore, the selectivity in cytokine responses is preserved downstream of TLR3, with inducible expression of Il-12p40 and IL-6, but not IFNβ, being SCIMP dependent. SCIMP is thus a universal TLR adaptor for scaffolding the Lyn tyrosine kinase and its effectors to enable responses against a wide range of danger signals.

Human hepatocellular carcinoma cells, HepG2, are often used for drug mediated mitochondrial toxicity assessments. Glucose in HepG2 culture media is replaced by galactose to reveal drug-induced mitochondrial toxicity as a marked shift of drug IC50 values for the reduction of cellular ATP. It has been postulated that galactose sensitizes HepG2 mitochondria by the additional ATP consumption demand in the Leloir pathway. However, our NMR metabolomics analysis of HepG2 cells and culture media showed very limited galactose metabolism. To clarify the role of galactose in HepG2 cellular metabolism, U-13C6-galactose or U-13C6-glucose was added to HepG2 culture media to help specifically track the metabolism of those two sugars. Conversion to U-13C3-lactate was hardly detected when HepG2 cells were incubated with U-13C6-galactose, while an abundance of U-13C3-lactate was produced when HepG2 cells were incubated with U-13C6-glucose. In the absence of glucose, HepG2 cells increased glutamine consumption as a bioenergetics source. The requirement of additional glutamine almost matched the amount of glucose needed to maintain a similar level of cellular ATP in HepG2 cells. This improved understanding of galactose and glutamine metabolism in HepG2 cells helped optimize the ATP-based mitochondrial toxicity assay. The modified assay showed 96% sensitivity and 97% specificity in correctly discriminating compounds known to cause mitochondrial toxicity from those with prior evidence of not being mitochondrial toxicants. The greatest significance of the modified assay was its improved sensitivity in detecting the inhibition of mitochondrial fatty acid β-oxidation (FAO) when glutamine was withheld. Use of this improved assay for an empirical prediction of the likely contribution of mitochondrial toxicity to human DILI (drug induced liver injury) was attempted. According to testing of 65 DILI positive compounds representing numerous mechanisms of DILI together with 55 DILI negative compounds, the overall prediction of mitochondrial mechanism-related DILI showed 25% sensitivity and 95% specificity.

NAC [no apical meristem (NAM), Arabidopsis transcription activation factor (ATAF1/2) and cup-shaped cotyledon (CUC2)] proteins is one of the largest classes of plant specific transcription factors and plays a critical role in plant growth, development process, and abiotic/biotic stresses. In this study, 73 NAC genes (AcNACs) were identified from the pineapple genome. Phylogenetic analysis showed that AcNACs could be divided into 13 subgroups. Gene structure analysis showed that the number of introns varied from 0 to 12. Motif analysis revealed that all of the identified AcNACs had the conserved NAC domain and motif 6 is the conserved motif. Most of the AcNACs were located in chromosome except AcNAC68, AcNAC70, AcNAC71 and AcNAC72, which were presented on unanchored scaffolds. Furthermore, we analysed AcNAC expression patterns in vegetative organs and in sexual organs, namely ovules and stamens, at different developmental stages respectively. Five AcNAC genes (AcNAC6; AcNAC7; AcNAC48; AcNAC70; AcNAC71) were not detected in vegetative organs. AcNAC55 exhibited the highest expression level in vegetative organs. Six AcNAC genes (AcNAC11, AcNAC18, AcNAC27, AcNAC28, AcNAC40, and AcNAC55) showed high expression levels in all reproductive organs. Seven AcNAC genes (AcNAC26, AcNAC34, AcNAC40, AcNAC43, AcNAC63 and AcNAC65) were induced under abiotic stresses. These data provided a new insight of NAC gene family in pineapple and revealed the diverse function of NAC transcription factors in pineapple growth and development.

Neurodegenerative diseases are among the most serious health problems affecting millions of people worldwide. Such diseases are characterized by a progressive degeneration and / or death of neurons in the central nervous system. Currently, there are no therapeutic approaches to cure or even halt the progression of neurodegenerative diseases. During the last two decades, much attention has been paid to the neuroprotective and anti-neurodegenerative activities of compounds isolated from natural products with high efficacy and low toxicity. Accumulating evidence indicates that berberine, an isoquinoline alkaloid isolated from traditional Chinese medicinal herbs, may act as a promising anti-neurodegenerative agent by inhibiting the activity of the most important pathogenic enzymes, ameliorating intracellular oxidative stress, attenuating neuroinflammation, triggering autophagy and protecting neurons against apoptotic cell death. This review attempts to summarize the current state of knowledge regarding the therapeutic potential of berberine against neurodegenerative diseases, with a focus on the molecular mechanisms that underlie its effects on Alzheimer’s, Parkinson’s and Huntington’s diseases.